Haemostasis system diseases, in particular thrombosis, vasoconstriction, play the key role in pathogenesis of coronary and cerebral blood circulation disturbances, that makes the treatment of mentioned diseases to be quite essential. The progress in therapy and prophylaxis of haemostasis disturbances is associated to a large extent with application of medical agents based on physiologically active compounds of different chemical nature and pharmacological action.
The prescription of antithrombotic drugs reduces the total risk of development of cardiovascular accidents by one quarter, nonfatal myocardial infarction by one third, nonfatal stroke by one quarter, vascular death by one sixth [McConnel H.//Br. Med. J. 2002. V. 324. P. 71-86]. In this case the basic ways of antithrombotic therapy are thrombocyte aggregation inhibition, aimed action on hemocoagulation system, reduction of endothelium thrombocyte activity. Despite the large amount of drugs capable to suppress thrombocyte activity and aggregation ability, their clinical efficiency against cardiovascular system diseases, that require antiaggregant treatment, is proven only in the case of three groups of agents—acetylsalicylic acid (ASA), thienopyridines (ticlopidine, clopidogrel, prasugrel), and thrombocyte glycoprotein receptor blockers.
Aspirin (acetylsalicylic acid—ASA) is considered as practically the only one drug that is applied for the purpose of primary cardiovascular disease prophylaxis [ANN Intern. Med. 2002. V. 136. P. 161-172], the efficiency and safety of which has been proved by the results of numerous investigations [Circulation. 2004. V. 110. P. 2361-2367; 30th International Stroke Conference. 2005, Abstr. P87].
The disadvantages of ASA should be attributed to prostacyclin synthesis suppression, bleeding risk, ASA-induced gastropathy that worsen tolerance and reduces the medication adherence by the patients, patient drug resistance [J. Thromb. Haemost. 2003. N1. P. 1710-1713; BMJ 2004. V. 328. P. 477-479; Brit. J. Clin. Pharmacol. 2008. V. 66. N2. P. 222-232].
The application of phosphodiesterase inhibitor—dipyridamole is known to reduce the frequency of ischemic transient attack development and strokes, lethality after cerebrovascular pathology. Dipyridamole has similar therapeutic effect to ASA; their combined application leads to the improvement of treatment efficiency [Future Medicine. 2005. V. 1. N1. P. 19-26]. However, dipyridamole application can provoke undesirable side effects. Thus, in the case of obstructing artery atherosclerosis and the presence of considerable amount of collaterals the drug can cause the development of steal syndrome. Therefore dipyridamole prescription is contraindicated in the case of critical coronary syndrome and myocardial infarction [Int. Med. J. 2008. V. 1. N1. P. 8-14].
Thienopyridine group representatives among antiaggregant agents are ticlopidine, clopidogrel, and prasugrel. These substances are prodrugs, it means that their therapeutic effect is achieved due to pharmacological activity of their active metabolites. The advantages of ticlopidine are reduction of stroke probability by 20%, reduction of its unfavorable outcomes and cerebral ischemia or vascular death by 10% [Ann. Intern. Med. 1998. V. 129. N5. P. 394-405]. The disadvantages of the drug are its low tolerance and frequently appearing dermal (4-15%) and gastrointestinal (up to 20%) reactions that lead to ticlopidine treatment cessation. Besides that lethal thrombocytopenic purpura cases are known [Bennett C., Weinberg P., Rozenberg-Ben-Dror K., et al. Thrombocytopenic purpura associated with ticlopidine. Ann Intern Med 1998; 128: 541-44].
Clopidogrel, according to CAPRIE [Lancet. 1996. V. 348. P. 1329-39], is more effective than aspirin in many cases of long-term treatment of patients with high risk of ischemic occurrences. Its advantages are better tolerance compared to ticlopidine, including lower frequency of hematological complications, faster therapeutic effect onset associated with stress dosing (300 and 600 mg), compatibility with majority of drugs used in cardiology. Clopidogrel disadvantages are resistance of patients with CYP450 polymorphism, especially 2C19 (up to 14% of population) [JACC. 2007. V. 49. P. 1505; FDA Drug Safety Communication. Mar. 12, 2010], considerable efficiency reduction when the drug is used together with proton pump inhibitors—omeprazole, rabeprazole [FDA Public-health advisory: Updated safety information about a drug interaction between clopidogrel bisulfate (marketed as Plavix) and omeprazole (marketed as Prilosec and Prilosec OTC). Nov. 17, 2009], suboptimal drug reaction of the patients with acute coronary syndrome, diabetes, and metabolic syndrome [JACC. 2007. V. 49. P. 1505].
Tikagrelor features relatively quick therapeutic effect onset and pronounced inhibition of thrombocyte aggregation activity. Tikagrelor treatment, compared to clopidogrel one, reduces the frequency of death caused by vascular pathologies, myocardial infarction and strokes with no increase of overall occurrence of large-scale bleedings, but with increase of bleeding occurrences that are not associated with invasive procedures. This is significant disadvantage of the drug that restricts its use [N. Engl. J. Med. 2009. V. 361. N11. P. 1045-57].
Likewise direct thrombin inhibitors—gatrans are used in clinical practice [Am. Heart J. 2009. V. 157. P. 805-810]. Dabigatran shows decrease in stroke risk (including hemorrhagic one), bleeding occurrences (including life threatening and intracranial ones), it also shows decrease in deaths caused by vascular incidents. The drug therapy does not require monitoring [N. Engl. J. Med. 2009. V. 361. N12. P. 1139-1151]. Significant disadvantages of this drug group representatives are hepatotoxicity, intragastric bleedings [NHS. 2009. N8], and also the lack of combined antiaggregant, anticoagulant, and vasodilatory action on the body.
The most similar drugs to the claimed invention in respect to achieved effects are thromboxane blockers—ridogrel, ozagrel, pirmagrel. They have antihypertensive and vasodilator properties. The drugs are safe and effective in case of myocardial infarction [Cardiovascular Drug Reviews. 2008. V18. N3. P. 222-231], and are capable to relieve bronchospasm [Life Science. 1997. V. 60. N18. P. 1583-88].
The disadvantage of this drugs group is low efficiency at oral introduction.
The aim that has been achieved by the authors is the creation of more effective and safe substances that possess combined antiaggregant, anticoagulant and vasodilator action on the body.